The field of the invention relates to 7-membered fused heterocycles and their methods of synthesis. In particular, the field of the invention relates to 7-membered fused heterocycles such as benzoxopinones, benzoxepanes, and benzoazepinones and methods of their synthesis.
Compounds comprising 7-membered fused heterocycles have been shown to be effective in a wide range of therapeutic applications. Benzoxepanes also are known to be central nervous system depressants. (See Porter et al., J. Psychopharmacology 2009, 203, 189). Benzodiazepine drugs such as Xanax® and Valium® are used to treat anxiety. (See Costanino et al., Benzodiazepines II; A Handbook; Spring: Berlin, 1989; Das et al., J. Med. Chem. 1992, 25 2610; and Floyd et al., J. Org. Chem. 1990, 5572). Further, benzazepinones are related to the FDA-approved drug diltiazem, which is a potent calcium channel blocker (Cardizem®) and SQ 31,486, a candidate to reduce myocardial ischemia for cardioprotective treatments. (See O'Connor et al., Fundam. Clin. Pharmacol. 1999, 13, 145; and Grover et al., J. Cardiovasc. Pharmacol. 1990, 16, 219).
Unfortunately, routes for synthesizing 7-membered fused heterocycles are scarce and the dearth of convergent strategies to access enantiopure scaffolds in good yields and selectivity has presumably hampered investigation of this class of compounds for its full therapeutic potential. Synthesis of 7-membered lactones through a formal [4+3] annulation has been reported recently. (See Lv et al., “N-Heterocyclic Carbene Catalyzed [4+3] Annulation of Enals and o-Quinone Methides: Highly Enantioselective Synthesis of Benzo-ε-Lactones.” Angew. Chem. doi: 10.1002/ange.201303903, Jul. 1, 2013). However, this reported synthesis method is designed only for the use of two specific stable-ortho-quinone methides which limits the synthesis method to a short range of modifications.
Here, a new dual activation strategy for synthesizing 7-membered fused heterocycles is reported. The strategy integrates a first Lewis Base (i.e., an N-heterocyclic carbene (NHC)) with a second Lewis base. The synthesis procedure combines a NHC-bound homoenolate equivalent derived from an α,β-unsaturated aldehyde with a transient reactive ortho-quinone methide generated by desilylation of a stably protected ortho-phenoxy silyl ether in an enantioselective formal [4+3] fashion to obtain a 2-benzoxopinone. This strategy represents a new synthetic approach to obtain 7-membered fused heterocycles using a variety of common starting materials such as α,β-unsaturated aldehydes and substituted, stably protected ortho-phenoxy ethers. The overall approach provides a general blueprint for the integration of carbene catalysis with additional Lewis base activation modes to obtain a variety of new 7-membered fused heterocycles.